U.S. patent number 5,298,258 [Application Number 07/899,278] was granted by the patent office on 1994-03-29 for acrylic oily gel bioadhesive material and acrylic oily gel preparation.
This patent grant is currently assigned to Nitto Denko Corporation. Invention is credited to Hitoshi Akemi, Yoshifumi Hosaka, Takashi Kinoshita, Yoshihisa Nakano, Saburo Otsuka.
United States Patent |
5,298,258 |
Akemi , et al. |
March 29, 1994 |
Acrylic oily gel bioadhesive material and acrylic oily gel
preparation
Abstract
An acrylic oily gel bioadhesive material comprising a substrate
having on one surface thereof a crosslinked gel layer formed by
crosslinking a composition comprising an acrylate polymer
comprising as a main component an alkyl (meth)acrylate having four
or more carbon atoms in the alkyl moiety and a liquid ingredient
compatible with said acrylate polymer.
Inventors: |
Akemi; Hitoshi (Osaka,
JP), Kinoshita; Takashi (Osaka, JP),
Otsuka; Saburo (Osaka, JP), Hosaka; Yoshifumi
(Osaka, JP), Nakano; Yoshihisa (Osaka,
JP) |
Assignee: |
Nitto Denko Corporation (Osaka,
JP)
|
Family
ID: |
27332460 |
Appl.
No.: |
07/899,278 |
Filed: |
June 16, 1992 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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635007 |
Dec 28, 1990 |
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Foreign Application Priority Data
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Dec 28, 1989 [JP] |
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1-344639 |
Sep 6, 1990 [JP] |
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2-237382 |
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Current U.S.
Class: |
424/484; 424/486;
424/487 |
Current CPC
Class: |
A61K
9/7061 (20130101); A61K 31/34 (20130101); A61K
31/565 (20130101); A61L 15/58 (20130101); A61L
15/58 (20130101); C08L 33/00 (20130101) |
Current International
Class: |
A61K
9/70 (20060101); A61L 15/58 (20060101); A61L
15/16 (20060101); A61K 31/34 (20060101); A61K
31/565 (20060101); A61K 009/14 () |
Field of
Search: |
;526/310 ;562/598
;525/330.2 ;424/484,78.26,78.34,78.18,484,486,487 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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0223524 |
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May 1987 |
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EP |
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0303445 |
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Feb 1989 |
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EP |
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0309404 |
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Mar 1989 |
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EP |
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0319988 |
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Jun 1989 |
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EP |
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1023895 |
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Mar 1966 |
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GB |
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2086224 |
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May 1982 |
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GB |
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Primary Examiner: Page; Thurman K.
Assistant Examiner: Kulkosky; Peter F.
Attorney, Agent or Firm: Sughrue, Mion, Zinn, Macpeak &
Seas
Parent Case Text
CROSS-REFERENCE TO THE RELATED APPLICATION
This application is a continuation-in-part application of U.S.
patent application Ser. No. 07/635,007 filed on Dec. 28, 1990,now
abandoned, entitled "ACRYLIC GEL MATERIAL AND ACRYLIC GEL
PREPARATION", now pending.
Claims
What is claimed is:
1. An acrylic oily gel bioadhesive material comprising a substrate
having on one surface thereof a crosslinked gel layer which is a
non-aqueous system formed by crosslinking a composition comprising
an acrylate polymer comprising as a main component an alkyl
(meth)acrylate having four or more carbon atoms in the alkyl moiety
and a liquid ingredient compatible with said acrylate polymer,
wherein the weight ratio of said acrylate polymer to said liquid
ingredient is from 1.0/0.25 to 1.0/2.0; said crosslinking is
effected by using a crosslinking agent selected from the group
consisting of a metal alcoholate and a metal chelate each
comprising titanium or aluminum, and trifunctional isocyanate; and
said acrylate polymer is selected from the group consisting of:
(a) a copolymer obtained by copolymerizing the alkyl (meth)acrylate
with at least one monomer represented by at least one of formulae
(I) and (II):
wherein R represents a hydrogen atom or a methyl group; X
represents a group having at least one nitrogen atom or a nitrogen
atom and an oxygen atom; Y represents a hydrogen atom or --COOR';
and R' represents a group having at least one nitrogen atom or a
nitrogen atom and an oxygen atom, or a hydroxy lower alkyl group,
and wherein the weight ratio of the alkyl (meth)acrylate to the at
least one monomer represented by at least one of formulae (I) and
(II) is (40-99)/(1-60);
(b) a copolymer obtained by copolymerizing the alkyl (meth)acrylate
with ate least one monomer containing at least one of a carboxyl
group and a hydroxyl group, and wherein the weight ratio of the
alkyl (meth)acrylate to the at least one monomer containing at
least one of a carboxyl group and a hydroxyl group is
(90-99)/(1-10); and
(c) a copolymer obtained by copolymerizing the alkyl (meth)acrylate
with at least one monomer represented by at least one of formulae
(I) and (II):
wherein R represents a hydrogen atom or a methyl group; X
represents a group having at least one nitrogen atom or a nitrogen
atom and an oxygen atom; Y represents a hydrogen atom or --COOR';
and R' represents a group having at least one nitrogen atom or a
nitrogen atom and an oxygen atom, or a hydroxy lower alkyl group,
and at least one monomer containing at least one of a carboxyl
group and a hydroxyl group, wherein the amount of said at least one
monomer containing at least one of a carboxyl group and a hydroxyl
group is 1 to 10% by weight based on the weight of the copolymer,
and wherein the weight ratio of the alkyl (meth)acrylate, the at
least one monomer represented by formulae (I) and (II), and the at
least one monomer containing at least one of a carboxyl group and a
hydroxyl group is (50-90)/(0-40)/(1-10).
2. An acrylic oily gel bioadhesive material as claimed in claim 1,
wherein the weight ratio of said acrylate polymer to said liquid
ingredient is from 1.0/0.4 to 1.0/2.0.
3. An acrylic oily gel bioadhesive material as claimed in claim 2,
wherein the weight ratio of said acrylate polymer to said liquid
ingredient is from 1.0/0.6 to 1.0//1.8.
4. An acrylic gel bioadhesive material as claimed in claim 1,
wherein said liquid ingredient compatible with said acrylate
polymer is selected from the group consisting of glycols, fats and
oils, organic solvents, liquid surfactants, hydrocarbons,
ethoxylated stearyl alcohol, glycerol esters, isopropyl myristate,
isotridecyl myristate, ethyl laurate, N-methyl-pyrrolidone, ethyl
oleate, oleic acid, isopropyl adipate, isopropyl palmitate, octyl
palmitate and 1,3-butanediol.
5. An acrylic oily gel preparation wherein a drug component is
contained in an acrylic oily gel bioadhesive material as claimed in
claim 1.
6. An acrylic oily gel preparation as claimed in claim 5, wherein
the content of said drug component is from 1 to 40% by weight based
on the total amount of said crosslinked gel layer.
7. An acrylic oily gel preparation as claimed in claim 6, wherein
the content of said drug component is from 3 to 30% by weight based
on the total amount of said crosslinked gel layer.
8. An acrylic oily gel preparation as claimed in claim 5, wherein
the thickness of said crosslinked gel layer is from 10 to 300
.mu.m.
9. An acrylic oily gel preparation as claimed in claim 8, wherein
the thickness of said crosslinked gel layer is from 40 to 150
.mu.m.
Description
FIELD OF THE INVENTION
The present invention relates to an acrylic oily gel bioadhesive
material which is applied to a surface of a skin so as to protect
the skin surface and an acrylic oily gel preparation which is used
to continuously administer a drug component to a living body via
the skin surface.
BACKGROUND OF THE INVENTION
Recently, various percutaneous preparations for external use in the
form of a preparation applied to the skin (for example, plaster,
tape), whereby a drug is administered to the living body via the
skin surface, have been developed.
Such a percutaneous preparation applied to the skin usually
involves an adhesive layer having a relatively large adhesiveness
to secure the fixation of the preparation on the skin surface.
Alternatively, the entire preparation is covered with a highly
adhesive sheet having a large adhesiveness which secures the
fixation of the preparation on the skin.
Although a percutaneous preparation applied to the skin should be
surely fixed on the skin so as to secure the migration of a drug
component into the skin, an excessively large adhesiveness might
bring about a pain or peeling of the horny substance caused by
physical stimulation upon the separation of the preparation from
the skin surface. Further, serious skin irritation is sometimes
observed.
Thus, the adhesiveness to the skin is an important factor in the
development of a percutaneous preparation in practice, and the
problem of the skin irritation is also an important factor.
Therefore, it has been practically required to develop a
preparation which scarcely irritates the skin and can be securely
fixed onto the skin.
SUMMARY OF THE INVENTION
Under these circumstances, the present inventors have conducted
extensive studies to overcome the above problems. As a result, it
has been found that a composition comprising an acrylate polymer
and a liquid ingredient compatible with the acrylate polymer, in
which the liquid ingredient is used in an amount larger than a
common level, can achieve a softness upon the adhesion to the skin.
However, it has been further found that such a composition as
described above suffers from a serious decrease in the cohesive
power and thus causes cohesion breakage, which makes the peeling of
the composition from the skin impossible or brings about skin
irritation. Thus, such a preparation cannot be used in practice.
Furthermore, it has been found that a decrease in the cohesive
power of the composition can be prevented and the stress applied to
the skin surface upon the separation of a composition can be
relieved and dispersed so as to achieve well-balanced skin
adhesiveness and skin irritativeness by crosslinking a polymer
layer containing an excessive amount of a liquid ingredient to
thereby form a so-called oily gel, thus completing the present
invention.
An object of the present invention is to provide an acrylic oily
gel bioadhesive material applied to the skin surface.
Another object of the present invention is to provide an acrylic
oily gel preparation capable of continuously administering a drug
component to the living body.
The present invention provides an acrylic oily gel bioadhesive
material comprising a substrate having on one surface thereof a
crosslinked gel layer formed by crosslinking a composition
comprising an acrylate polymer comprising as a main component an
alkyl (meth)acrylate having 4 or more carbon atoms and a liquid
ingredient compatible with the acrylate polymer.
The present invention also relates to an acrylic oily gel
preparation wherein a drug component is contained in the above
acrylic oily gel bioadhesive material.
DETAILED DESCRIPTION OF THE INVENTION
The substrate used in the acrylic oily gel bioadhesive material and
the acrylic oily gel preparation of the present invention is not
particularly limited, but materials which would never suffer from
any decrease in the content of the liquid ingredient or the drug
contained in the crosslinked gel layer caused by the migration
toward another face of the substrate followed by leakage, are
preferably used. Examples thereof include sole films of polyester,
nylon, Saran resins, polyethylene, polypropylene, ethylene-vinyl
acetate copolymer, polyvinyl chloride, ethylene-ethyl acrylate
copolymer, polytetrafluoroethylene, Surlyn resins and metal foils,
and laminate films comprising these materials. Of those, it is
preferred to use a substrate in the form of a laminate film
composed of a nonporous sheet comprising one or more materials as
described above and a porous film and to form a crosslinked gel
layer on the surface of the porous sheet, to thereby improve the
adhesiveness between the substrate and the crosslinked gel layer by
the anchoring effect which will be described hereinbelow.
The material of the porous film is not particularly restricted so
long as the anchoring effect to the crosslinked gel layer can be
improved. Examples thereof include paper, woven fabric, nonwoven
fabric and mechanically perforated sheet. It is particularly
preferred to use paper, woven fabric and nonwoven fabric. When the
improvement of the anchoring effect and the flexibility of the
whole preparation are taken into consideration, the thickness of
the porous film is preferably from 10 to 500 .mu.m, and in the case
of a thin preparation such as plaster or tape, it is more
preferably from 10 to 200 .mu.m. When the laminate film composed of
the above porous film and the nonporous sheet is used as the
substrate, the thickness of the nonporous sheet is preferably from
0.5 to 50 .mu.m, and more preferably from 1 to 25 .mu.m.
When woven fabric or nonwoven fabric is used as the porous film,
the weight per unit area of the woven or nonwoven fabric is
preferably from 5 to 30 g/m.sup.2, more preferably from 8 to 20
g/m.sup.2, from the standpoint of the improvement on the anchoring
effect.
In the present invention, the crosslinked gel layer formed on one
surface of the substrate is a layer of a crosslinked structure
obtained by crosslinking a composition comprising an acrylate
polymer and a liquid ingredient compatible with the acrylate
polymer together with, in the case of a preparation, a drug
component, and having an appropriate adhesiveness to the skin and
an appropriate cohesive power. The adhesiveness is generally from
40 o 250 g/12 mm width in terms of the adhesiveness to a bakelite
plate (the determination method therefor will be described in
detail hereinafter) and from 20 to 80 g in the probe-tack test.
The acrylate copolymer serves as a main component constituting the
crosslinked gel layer together with the liquid ingredient which
will be described in detail hereinafter. It sustains a high
compatibility with the liquid ingredient and thus shows an
excellent adhesiveness to the skin surface as well as an excellent
shape retention. In the present invention, it is not preferred to
use rubber such as natural or synthetic rubber or a silicone
polymer since these materials have a poor compatibility with the
liquid ingredient used in the present invention or show a
considerably low solubility or release of the drug component. In
addition, it is difficult to control the amount of functional
groups participating in the crosslinking of such a polymer, as
compared with the acrylate polymer used in the present invention,
and thus highly reproducible crosslinking can hardly be achieved.
These facts indicate that the abovedescribed polymers are
unsuitable in the present invention.
The acrylate polymer used in the present invention is a polymer of
an alkyl (meth)acrylate having 4 or more carbon atoms in the alkyl
moiety. It is particularly preferred, from the standpoint of the
convenience in the crosslinking, to use a copolymer obtained using
the alkyl (meth)acrylate as the main component.
The terms "(meth)acrylate", etc. used herein mean "acrylate and/or
methacrylate", etc.
Examples of the alkyl (meth)acrylate include (meth)acrylates having
straight-chain or branched alkyl groups, for example, butyl,
pentyl, hexyl, heptyl, octyl, nonnyl, decyl, undecyl, dodecyl and
tridecyl. Either one or more of these (meth)acrylates can be used.
Of these, 2-ethylhexyl acrylate, isooctyl acrylate and isononyl
acrylate are preferably used.
Examples of a monomer to be copolymerized with the alkyl
(meth)acrylate include monomers containing a carboxyl group, such
as (meth)acrylic acid, itaconic acid, maleic acid and maleic
anhydride; monomers containing a sulfoxyl group, such as
styrenesulfonic acid, allylsulfonic acid, sulfopropyl
(meth)acrylate, (meth)acryloyloxynaphthalenesulfonic acid and
acrylamidemethyl propanesulfonic acid; monomers containing a
hydroxyl group, such as hydroxyethyl (meth)acrylate and
hydroxypropyl (meth)acrylate; monomers containing an amide group,
such as (meth)acrylamide, diacetone acrylamide,
dimethyl(meth)acrylamide, N-butylacrylamide,
N-methylol(meth)acrylamide and N-methylolpropane(meth)acrylamide;
monomers containing an alkylaminoalkyl group, such as aminoethyl
(meth)acrylate, dimethylaminoethyl (meth)acrylate and
tert-butylaminoethyl (meth)acrylate; alkoxyalkyl (meth)acrylates
such as methoxyethyl (meth)acrylate and ethoxyethyl (meth)acrylate;
(meth)acrylates containing an alkoxy group (or an ether bond in a
side chain), such as tetrahydrofurfuryl (meth)acrylate,
methoxyethylene glycol (meth)acrylate, methoxydiethylene glycol
(meth)acrylate, methoxypolyethylene glycol (meth)acrylate and
methoxypolypropylene glycol (meth)acrylate; and vinyl monomers such
as (meth)acrylonitrile, vinyl acetate, vinyl propionate,
N-vinylpyrrolidone, methyl vinyl pyrrolidone, vinyl pyridine, vinyl
piperidine, vinyl pyrimidine, vinyl piperazine, vinyl pyrazine,
vinyl pyrol, vinyl imidazole, vinyl caprolactam, vinyl oxazole and
vinyl morpholine. Of the above, (meth)acrylic acid, hydroxyethyl
(meth)acrylate, 2-methoxyethyl acrylate, acrylamide,
N-vinyl-2-pyrrolidone and diacetone acrylamide are preferably used.
Either one of these substances or a mixture thereof can be used in
the copolymerization. These copolymerizable monomers are used to
control the cohesive power of the gel layer and improve the
solubility of the drug. The amounts of these monomers can be
arbitrarily selected depending on the purpose.
Of the above-described acrylate polymers, a copolymer obtained by
copolymerizing the alkyl (meth)acrylate with monomer(s) represented
by formulae (I) and/or (II):
wherein R represents a hydrogen atom or a methyl group; X
represents a group having at least one nitrogen atom or a nitrogen
atom and an oxygen atom; Y represents a hydrogen atom or --COOR';
and R' represents a group having at least one nitrogen atom or a
nitrogen atom and an oxygen atom, or a hydroxyl lower alkyl group,
is preferably used in the present invention. By copolymerizing the
monomers represented by formulae (I) and (II), the extent of
crosslinking and the properties of the gel obtained can be
controlled. The weight ratio of the (meth)acrylate to the
monomer(s) of formulae (I) and/or (II) is preferably
(40-99)/(1-60), more preferably (60-98)/(2-40) while the total
amount of these monomers being 100.
It is also preferred in the present invention to use as the
acrylate copolymer a copolymer obtained by copolymerizing the alkyl
(meth)acrylate and monomer(s) containing a carboxyl group and/or a
hydroxyl group. The weight ratio of the alkyl (meth)acrylate to the
monomer(s) containing a carboxyl group and/or a hydroxyl group is
(90-99)/(1-10). The monomer(s) containing a carboxyl group and/or a
hydroxyl group is a component which improves a cohesive power and
an adhesiveness of the gel layer.
It is more preferred in the present invention to use as the
acrylate polymer a copolymer obtained by copolymerizing the alkyl
(meth)acrylate, the monomer(s) of the formulae (I) and/or (II) as
defined above, and monomer(s) containing a carboxyl group and/or a
hydroxyl group. The amount of the monomer(s) containing a carboxyl
group and/or a hydroxyl group is preferably 1 to 10% by weight
based on the weight of the copolymer obtained. In this case, the
weight ratio of the alkyl (meth)acrylate, the monomer(s) of
formulae (I) and/or (II), and the monomer(s) containing a carboxyl
group and/or a hydroxyl group is (50-99)/(0-40)/(1-10).
The liquid ingredient used in the present invention has a high
compatibility with the acrylate copolymer. The liquid ingredient
appropriately plasticizes the crosslinked gel layer and thus
imparts a flexible texture to the layer to thereby relive a pain or
skin irritativeness caused by the skin adhesiveness upon the
separation of the crosslinked gel layer from the skin surface.
Therefore, the liquid ingredient can be selected from materials
having a plasticizing effect. A substance which further has an
absorption-promoting effect can preferably be selected to improve
the percutaneous absorption of the drug component used
together.
Examples of the liquid ingredient include glycols such as ethylene
glycol, diethylene glycol, triethylene glycol, propylene glycol,
polyethylene glycol and polypropylene glycol; fats and oils such as
olive oil, castor oil, squalene and lanolin; organic solvents such
as dimethyl decyl sulfoxide, methyl octyl sulfoxide, dimethyl
sulfoxide, dimethylformamide, dimethylacetamide,
dimethyllaurylamide, dodecyl pyrrolidone and isosorbitol; liquid
surfactants; plasticizers such as diisopropyl adipate, phthalates
and diethyl sebacate; hydrocarbons such as liquid paraffin;
ethoxylated stearyl alcohol, glycerol esters, isopropyl myristate,
isotridecyl myristate, ethyl laurate, N-methylpyrrolidone, ethyl
oleate, oleic acid, isopropyl adipate, isopropyl palmitate, octyl
palmitate and 1,3-butanediol. Of the above, phthalates, isopropyl
myristate, isotridecyl myristate and octyl palmitate are preferably
used. These substances can be used alone or as a mixture
thereof.
The acrylate polymer and the liquid ingredient are contained in the
crosslinked gel layer at a weight ratio of preferably from 1.0/0.25
to 1.0/2.0, more preferably from 1.0/0.4 to 1.0/2.0 and most
preferably from 1.0/0.6 to 1.0/1.8, from the standpoint of reducing
the skin irritativeness. Namely, it is preferred to use a
considerably large amount of the liquid ingredient. In contrast, a
conventional preparation usually contains a liquid ingredient at a
weight ratio less than 1.0/0.25. Such a low content of the liquid
ingredient would sometimes make it impossible to achieve a
satisfactory low level of the skin irritativeness, from a practical
standpoint.
In the present invention, the composition thus-obtained is then
crosslinked by an appropriate crosslinking procedure to prepare a
gel, thus preventing the leakage of the liquid ingredient contained
in the preparation and imparting a cohesive power, as described
above. The crosslinking can be effected by a physical means such as
irradiation (for example, UV irradiation or electron beam
irradiation) or a chemical means using a crosslinking agent (for
example, polyisocyanate compound, organic peroxide, organic metal
salt, metal alcoholate, metal chelate compound, polyfunctional
compound).
Of these crosslinking procedures, irradiation or use of an organic
peroxide might induce decomposition in the cases of some drug
component. Further, the use of a highly reactive isocyanate or a
metal salt or an organic metal salt commonly used in crosslinking
reaction might sometimes cause an increase in the viscosity of the
solution, which lowers the workability thereof. It is also possible
to preliminarily copolymerize a polyfunctional monomer such as
diacrylate with the acrylate polymer. In this case, however, there
is a possibility that the viscosity of the solution would increase
at the polymerization.
In the present invention, therefore, it is preferred to select
trifunctional isocyanate or a metal alcoholate or a metal chelate
compound comprising titanium or aluminum from the above-described
crosslinking agents, from the standpoints of reactivity and
handling. These crosslinking agents would not cause any increase in
the viscosity of the solution until the completion of the
application and drying, which means that they are excellent in
workability. When these crosslinking agents are used, the
crosslinking reaction can be effected to a certain extent by
coating and drying the gel layer, but the coated and dried gel
layer is preferably aged at from 40.degree. to 70.degree. C. to
stabilize the properties of the gel layer. The aging time varies
depending on the addition amount and the kind of the functional
groups of the crosslinking agent, and is generally from 2 to 3
days. Such a crosslinking agent is preferably used in an amount of
from 0.01 to 2.0 parts by weight per 100 parts by weight of the
acrylate polymer. When the acrylate polymer does not have a
functional group which reacts with the above-described crosslinking
agent, the material to be crosslinked may be modified by, for
example, treating with an alkali to thereby enable the
crosslinking.
In the present invention, a drug component can be added to the
crosslinked gel layer thus-obtained to thereby prepare an oily gel
preparation. The drug component added can be arbitrarily selected
depending on the purpose of the treatment. Namely, any drug
component can be used so long as it can be percutaneously absorbed.
Examples thereof include cortisteroid, analgesic/antiinflammatory
agent, hypnotic/sedative agent, ataraxic, antihypertensive agent,
hypotensive diuretic, antibiotic, anesthetic, antibacterial agent,
fungicide, vitamin preparation, coronary dilator (except isosorbide
dinitrate), antihistamine, antitussive agent, sex hormone (except
estrogen), antidepressant, cerebral circulatory improver,
antivommiting agent, antitumor agent and biogenic. These drugs can
be used alone or as a mixture thereof. To achieve the uniform
dispersion in the crosslinked gel layer and promote percutaneous
absorption, it is preferred to select and use a hydrophobic drug
(having a solubility of 0.4 g/100 ml of water or less at room
temperature) from the above-described drug components.
The content of the drug component can be appropriately determined
depending on the drug component selected and the purpose of the
administration. It is generally contained in the crosslinked gel
layer in an amount of from 1 to 40% by weight, preferably from 3 to
30% by weight, based on the weight of the crosslinked gel layer. If
the content of the drug is smaller than 1% by weight, the release
of a therapeutically effective amount of the drug cannot be
expected. If it is exceeds 40% by weight, on the other hand, no
improvement in the effect cannot be achieved any more. Thus, both
of these cases bring about economical disadvantages.
The method for preparing the oily gel material and the oily gel
preparation according to the present invention is not particularly
limited. For example, a drug solution is added to a solution of an
acrylate polymer followed by stirring, and a liquid ingredient is
added thereto to from a uniform solution. A crosslinking agent in
the form of a solution is added to the above-obtained solution and
the viscosity of the resulting solution is adjusted by ethyl
acetate to prepare a gel layer coating composition. The coating
composition is coated on a separator, and then dried to form an
oily gel layer. The thickness of the oily gel layer after drying is
preferably from 10 to 300 .mu.m, and more preferably from 40 to 150
.mu.m. The resulting oily gel layer is transferred to a substrate,
and then, if necessary, aged at from 40.degree. to 70.degree. C. to
obtain an oily gel preparation according to the present invention.
An oily gel bioadhesive material according to the present invention
can be prepared in the same manner as above except that the drug
solution is not used.
When the drug component is added to the acrylic oily gel
preparation of the present invention, it is preferred that the
crosslinked gel layer contains the drug as described above.
Alternatively, it is possible that the drug component is not
contained in the crosslinked gel layer but is dissolved in an
appropriate solvent, and the solution thus-obtained is located at
the interface between the crosslinked gel layer and the substrate,
followed by sealing the periphery of the preparation. When the
layer containing the drug component is separated from the
cross-linked gel layer in the manner as described above, the
decomposition of the drug component upon storage can be suppressed
in the case of a drug component which is liable to undergo
decomposition. In this case, the release of the drug component can
be severely controlled by locating a microporous film between the
layer containing the drug component and the crosslinked gel
layer.
Each of the acrylic oily gel bioadhesive material and the acrylic
oily gel preparation of the present invention, which has the
above-described structure, comprises a crosslinked gel layer
containing a large amount of the liquid ingredient compatible with
the acrylate polymer. Thus, it is possible to impart a flexibility
to the crosslinked gel layer and to reduce the skin irritativeness
while maintaining the cohesive power of the gel layer. When the
preparation of the present invention is separated from the surface
of the skin, therefore, the pain and skin irritativeness caused by
the adhesiveness can be reduced. Thus, the percutaneous gel
preparation of the present invention has well-balanced adhesiveness
to the skin and nonirritativeness. Further, the acrylic oily gel
preparation containing a drug component can appropriately release
the drug component onto the surface of the skin. Thus, it is useful
to prevent and treat various diseases through the percutaneous
administration of the drug component.
In the present invention, the standard of the painless removal of
the oily gel preparation from the surface of the skin is specified
as follows. In a peeling test by volunteers, the amount of the
peeled horny substance caused by the removal of the preparation of
the present invention corresponds to 1/5 to 2/3 of those observed
in the case of control preparations free from any liquid
ingredient. When the amount of the peeled horny substance is
outside the above range, either a pain or an insufficient
skin-adhesion might be caused.
The present invention will be described in more detail by reference
to the following Examples and Comparative Examples, but the present
invention is not construed as being limited thereto. In the
following Examples and Comparative Examples, all parts and percents
are by weight.
EXAMPLE 1
95 Parts of 2-ethylhexyl acrylate and 5 parts of acrylic acid were
copolymerized in ethyl acetate under an inert gas atmosphere to
prepare an acrylate polymer solution.
To 50 parts of the solid content of the above solution, 50 parts of
isopropyl myristate was added. To 99.8 parts of the above acrylic
polymer, 0.2 parts of aluminum tris(acetylacetonate) which was in
the form of a 10% solution in acetylacetone was added. Further,
ethyl acetate was added thereto to adjust the viscosity of the
mixture.
The viscous solution thus-obtained was applied to a polyester
separator (thickness: 75 .mu.m) at a dry thickness of 80 .mu.m.
After drying and crosslinking, a crosslinked gel layer was
formed.
The crosslinked gel layer thus-obtained was adhered to the nonwoven
fabric face of a laminate film (i.e., a substrate), which was
obtained by extruding polyester having a thickness of 2 .mu.m on a
polyester nonwoven fabric (12 g/m.sup.2). Thus, an acrylic oily gel
bioadhesive material of the present invention was obtained.
EXAMPLE 2
The procedure of Example 1 was repeated except that 45 parts of
isopropyl myristate and 10 parts of ketoprofen were added to 45
parts of the solid content of the acrylate polymer obtained in
Example 1. Thus, an acrylic oily gel preparation of the present
invention was obtained.
EXAMPLE 3
The procedure of Example 2 was repeated except that the isopropyl
myristate was replaced by octyl palmitate. Thus, an acrylic oily
gel preparation of the present invention was obtained.
COMPARATIVE EXAMPLE 1
The procedure of Example 1 was repeated except that the acrylate
polymer prepared in Example 1 was not subjected to the crosslinking
but was directly used. Thus, an acrylic gel material containing the
liquid ingredient was obtained.
This acrylic gel material was broken because of low cohesion power.
Thus, it was impossible to subject the material to any of the tests
which will be described hereinafter
COMPARATIVE EXAMPLE 2
The procedure of Example 1 was repeated except that 10 parts of
ketoprofen was added to 90 parts of the solid content of the
acrylate polymer solution prepared in Example 1, followed by adding
ethyl acetate, to adjust the viscosity. Thus, an uncrosslinked
acrylic preparation free from any liquid ingredient was
obtained.
COMPARATIVE EXAMPLE 3
The procedure of Comparative Example 2 was repeated except that 0.2
part of a crosslinking agent (aluminum tris(acetylacetonate)) was
added to the polymer solid content. Thus, a crosslinked acrylate
preparation free from any liquid ingredient was obtained.
EXAMPLE 4
75 Parts of 2-ethylhexyl acrylate, 23 parts of
N-vinyl-2-pyrrolidone and 2 parts of acrylic acid were
copolymerized in ethyl acetate under an inert gas atmosphere to
prepare an acrylate polymer solution.
To 50 parts of the solid content of the above solution, 50 parts of
octyl palmitate was added. To 99.8 parts of the above acrylic
polymer, 0.2 parts of ethylacetoacetate aluminum diisopropylate
which was in the form of a 10% solution in acetylacetone was added.
Further, ethyl acetate was added thereto to adjust the viscosity of
the mixture.
The viscous solution obtained above was treated in the same manner
as in Example 1 to prepare an acrylic oily gel bioadhesive material
of the present invention.
EXAMPLE 5
The procedure of Example 4 was repeated except that 40 parts of
octyl palmitate and 15 parts of nifedipine were added to 45 parts
of the solid content of the acrylate polymer prepared in Example 4.
Thus, a crosslinked gel layer was formed.
The same procedure as in Example 1 was followed except that the
polyester film used as a substrate in Example 1 on which aluminum
was vapor-deposited for light shielding was used. Thus, an acrylic
oily gel preparation of the present invention was obtained.
EXAMPLE 6
The procedure of Example 5 was repeated except that octyl palmitate
was replaced with isotridecyl myristate. Thus, an acrylic oily gel
preparation of the present invention was obtained.
COMPARATIVE EXAMPLE 4
The procedure of Example 4 was repeated except that the acrylate
polymer prepared in Example 4 was not subjected to the crosslinking
but was directly used. Thus, an uncrosslinked acrylic gel plaster
free from any liquid ingredient was obtained.
This acrylic gel plaster was broken because of low cohesive power.
Thus, it was impossible to subject the plaster to any of the tests
which will be described hereinafter.
COMPARATIVE EXAMPLE 5
The procedure of Example 4 was repeated except that 15 parts of
nifedipine was added to 85 parts of the solid content of the
acrylate polymer solution prepared in Example 4, followed by adding
ethyl acetate, to adjust the viscosity. Thus, an uncrosslinked
acrylic preparation free from any liquid ingredient was
obtained.
COMPARATIVE EXAMPLE 6
The procedure of Comparative Example 5 was repeated except that 0.2
part of a crosslinking agent (ethylacetoacetate aluminum
diisopropylate) was added to the polymer solid content. Thus, a
crosslinked acrylate preparation free from any liquid ingredient
was obtained.
COMPARATIVE EXAMPLE 7
The procedure of Comparative Example 4 was repeated except that the
acrylate polymer used in Comparative Example 4 was replaced with a
polyisobutyrene rubber polymer comprising 10 parts of
polyisobutyrene (viscosity-average molecular weight: 990,000), 15
parts of polyisobutyrene (viscosity-average molecular weight:
60,000), 3 parts of polyisobutyrene (viscosity-average molecular
weight: 1260) and 7 parts of an alicyclic petroleum resin
(softening point: 100.degree. C.), and ethyl acetate was replaced
with toluene. Thus, a rubber gel preparation was obtained.
This gel preparation showed precipitation of a large amount of
nifedipine immediately after the completion of the preparation.
EXAMPLE 7
70 Parts of 2-ethylhexyl acrylate, 25 parts vinyl acetate and 5
parts of 2-hydroxyethyl methacrylate were copolymerized in ethyl
acetate under an inert gas atmosphere to prepare an acrylate
polymer solution.
To 50 parts of the solid content of the above solution, 50 parts of
isotridecyl myristate was added. To 99.7 parts of the above acrylic
polymer, 0.3 parts of trifunctional isocyanate ("Coronate HL"
manufactured by Nippon Polyurethane Co., Ltd.) in the form of a 10%
solution in ethyl acetate was added. Further, ethyl acetate was
added thereto to adjust the viscosity.
The viscous solution thus-obtained was treated in the same manner
as in Example 1 to prepare an acrylic oily gel bioadhesive material
of the present invention.
EXAMPLE 8
The procedure of Example 7 was repeated except that 45 parts of
tridecyl myristate and 10 parts of clonidine were added to 45 parts
of the solid content of the acrylate polymer prepared in Example 7
and 0.3 part of trifunctional isocyanate ("Coronate HL"
manufactured by Nippon Polyurethane Co., Ltd.) in the form of a 10%
solution in ethyl acetate was added to 99.7 parts of the acrylate
polymer. Thus, a crosslinked gel layer was formed. The crosslinked
gel layer was adhered to the same type of the substrate as used in
Example 1 to prepare an acrylic gel oily preparation of the present
invention.
EXAMPLE 9
The procedure of Example 8 was repeated except that isotridecyl
myristate was replaced with isopropyl myristate. Thus, an acrylic
oily gel preparation of the present invention was obtained.
COMPARATIVE EXAMPLE 8
The procedure of Example 7 was repeated except that the
crosslinking agent was not added. Thus, an uncrosslinked acrylic
gel material containing a liquid ingredient was obtained.
This acrylic gel material was broken because of low cohesive power.
Thus, it was impossible to subject the material to any of the tests
which will be described hereinafter.
COMPARATIVE EXAMPLE 9
The procedure of Example 7 was repeated except that 0.3 part of
trifunctional isocyanate ("Coronate HL" manufactured by Nippon
Polyurethane Co., Ltd.) in the form of a 10% solution in ethyl
acetate was added to 99.7 parts of the solid content of the
acrylate polymer solution prepared in Example 7, followed by
adjusting the viscosity with ethyl acetate. Thus, a crosslinked
acrylic plaster free from any liquid ingredient was obtained.
COMPARATIVE EXAMPLE 10
The procedure of Example 7 was repeated except that 10 parts of
clonidine was added to 90 parts of the solid content of the
acrylate polymer solution prepared in Example 7 and 0.3 part of
trifuctional isocyanate ("Coronate HL" manufactured by Nippon
Polyurethane Co., Ltd.) in the form of a 10% solution in ethyl
acetate was added to 99.7 parts of the solid content of the
acrylate polymer solution prepared in Example 7, followed by
adjusting the viscosity with ethyl acetate. Thus, a crosslinked
acrylic preparation free from any liquid ingredient was
obtained.
COMPARATIVE EXAMPLE 11
By using the acrylate polymer solution prepared in Example 1, a
plaster which did contain the liquid ingredient, crosslinking agent
and drug component was prepared. The substrate used was the same
type as used in Example 1.
COMPARATIVE EXAMPLE 12
The procedure of Example 1 was repeated except that 18 parts of
isopropyl myristate was added to 82 parts of the solid content of
the acrylate polymer solution. Thus, an acrylic gel material was
obtained.
COMPARATIVE EXAMPLE 13
20 Parts of CARBOPOL.RTM. 940 (molecular weight: 4,000,000), 40
parts of isopropyl myristate and 10 parts of an ethoxidized
nonionic surfactant (TERGITOL 15-15-12, manufactured by Union
Carbide Co.) were dissolved in 10 parts of water, and the resulting
mixture was stirred. However, since isopropyl myristate did not
dissolve in water, CARBOPOL and the isopropyl myristate were not
mixed and it was impossible to prepare a gel material.
COMPARATIVE EXAMPLE 14
5 Parts of CARBOPOL 940 was dissolved in 35 parts of water with
stirring. The resulting solution was allowed to stand at room
temperature for 24 hours.
Separately, a solution was prepared by dissolving 30 parts of
isopropyl myristate and 10 parts of TERGITOL 15-15-12 into 20 parts
of water. This solution was mixed with the solution obtained above,
and the mixed solution was stirred with a high speed disper.
After degassing, the solution was flow-cast on a metallic mold
having a depth of 3 mm, and heated at 50.degree. C. for 1 hour to
gel the solution. The gel layer is laminated on the same type of
the substrate as used in Example 1 to prepare a gel material.
This gel material showed severe oozing of isopropyl myristate and
did not substantially have adhesiveness to the skin. Therefore, it
was impossible to subject the gel material to any of the tests.
COMPARATIVE EXAMPLE 15
A 30% polyhydroxyethyl methacrylate in dimethyl formamide was
flow-cast on a Teflon plate, and dried to obtain a film having a
thickness of about 100 .mu.m.
0.3 g of 30-40 mesh sieve pass CARBOPOL 940 was introduced in 60 ml
of a water/dimethyl formamide (3/1) mixed solution. 10 ml of this
solution was uniformly sprayed on a piece of 50 cm.sup.2 (7.1
cm.times.7.1 cm) obtained by cutting the film obtained above and
wetting with dimethyl formamide, and dried at room temperature to
prepare a gel material.
This material did not have adhesiveness to the skin, and it was
impossible to subject the material to any of the tests.
COMPARATIVE EXAMPLE 16
The gel material obtained in Comparative Example 15 above was
dipped in water for 1 hour to wet the same. The wet gel material
had a relatively good adhesiveness to the skin. However, the gel
material had a very weak adhesive strength and easily separated
from the skin. Further, the adhesive layer portion thereof was
broken by a slight force because of low cohesion power. Therefore,
it was impossible to subject the wet gel material to any of the
tests.
Further, the wet gel material had the tendency to dry easily, and
moisture in the gel material volatilized during bonding to the
skin, thereby losing the adhesive strength.
TEST EXAMPLE
Each of the gel materials and gel preparations obtained in the
above Examples and Comparative Examples was stored at 40.degree. C.
under a relative humidity of 75% for 2 weeks. These samples were
then subjected to the following tests. In the determination of the
peeled horny substance, samples comprising a single-layer film
(thickness: 9 .mu.m) having no nonwoven fabric laminated as the
substrate were employed, since the absorption of the dyeing
solution by the nonwoven fabric in the substrate might
substantially lower the accuracy of the determination. Further, the
preparations containing clonidine were not subjected to the human
patch test. Tables 1 and 2 show the results.
Rabbit Patch Test
Each of the samples obtained in the Examples and the Comparative
Examples was applied onto the dorsal part of a rabbit from which
the hair had been removed. Then, 2 mol portions of the blood of the
rabbit were collected after 1.0, 2.5, 4.0, 6.0 and 8.0 hours, and
the concentration of isosorbide dinitrate in each blood sample was
determined by gas chromatography. The samples containing clonidine
were cut into a piece of 3 cm.sup.2 (1.73 cm.times.1.73 cm) while
the others were cut into a piece of 50 cm.sup.2 (7.1 cm.times.7.1
cm).
ADHESION TEST
Each sample in the form of a strip of 12 mm in width was applied to
a bakelite plate. Then, a roller of a load of 300 g was moved
thereon back and force to secure the adhesion of the sample to the
plate. Subsequently, the sample was peeled off in the direction of
180.degree. C. at a rate of 300 mm/min, and the peeling force upon
this procedure was measured.
Tack Test
The tack of each sample was evaluated by the probe tack method with
a rheometer.
The sample was fixed on a metal plate in a manner such that the
face to be adhered to the skin was placed upward. Then, a spherical
probe (diameter: 10 mm) was contacted with the sample under a load
of 100 g at a rate of 2 cm/min. After maintaining this state for 20
seconds, the spherical probe was separated therefrom at the same
rate. The peeling force upon this procedure was measured.
Pain At Peeling
Samples were applied to the inside of upper arms of 5 volunteers.
After 30 minutes, the samples were peeled off and the pain thus
caused was examined. The pain was evaluated in five grades (1: the
least pain) and expressed in the average of the volunteers. As a
standard, the sample prepared in Comparative Example 1 was referred
to as 5.
Peeled Horny Substance
Circular samples (diameter: 16 mm) were applied to the inside of
upper arms of 3 volunteers (A, B and C). After 30 minutes, the
samples were peeled off and immersed in a dyeing solution composed
of 0.5% of Gentian violet, 0.5% of Brillian green and 98.5% of
distilled water for 3 minutes, followed by washing with water, to
dye horny cells.
These samples were then immersed in a 5% aqueous solution of sodium
dodecyl sulfate over day and night to extract the dyeing solution.
The absorbance of the extract was measured at 595 nm to compare the
number of the peeled horny cells. That is, it was considered that a
higher absorbance would indicate the larger amount of the peeled
horny substance.
A good correlation was observed between the number of the peeled
horny cells counted with a stereoscopic microscope and the
above-described absorbance.
TABLE 1 ______________________________________ Rabbit patch test
Maximum Time required for blood level achieving maximum (ng/ml)
blood level (hour) ______________________________________ Example 2
2,970 2.0 Example 3 2,840 2.0 Example 5 205 4.0 Example 6 198 4.0
Example 8 16 6.0 Example 9 20 6.0 Comparative 1,840 2.0 Example 2
Comparative 1,510 2.0 Example 3 Comparative 58 4.0 Example 5
Comparative 49 4.0 Example 6 Comparative 11 4.0 Example 7
Comparative 8 6.0 Example 10
______________________________________
TABLE 2 ______________________________________ Adhesive- Peeled
horny ness Tack substance(*) (g) (g) Pain A B C
______________________________________ Example 1 184 45 1.6 43.4
44.4 27.4 Example 2 176 43 1.6 48.7 40.1 33.8 Example 3 181 44 1.8
42.2 39.5 34.1 Example 4 156 38 1.4 35.1 38.6 29.9 Example 5 142 34
1.4 37.2 36.6 35.5 Example 6 180 44 1.6 49.1 45.5 28.7 Example 7
151 36 1.2 36.1 37.2 31.3 Example 8 154 37 -- -- -- -- Example 9
132 32 -- -- -- -- Comparative 532 129 5.0 148 162 131 Example 2
Comparative 516 125 5.0 162 181 141 Example 3 Comparative 451 109
4.6 159 132 124 Example 5 Comparative 484 117 4.8 179 132 138
Example 6 Comparative 1,187 282 5.0 140 70.1 72.2 Example 7
Comparative 421 102 4.6 141 125 119 Example 9 Comparative 432 105
-- -- -- -- Example 10 Comparative 529 138 5.0 151 192 138 Example
11 Comparative 531 140 4.6 141 106 122 Example 12
______________________________________
As is apparent from Tables 1 and 2 above, the acrylic oily gel
bioadhesive material and the acrylic oily gel preparation of the
present invention show less pain at the peeling and also suffer
from the peeling of a smaller amount of the horny substance, as
compared with the products of Comparative Examples. Further, it is
apparent that in the gel preparation containing the drug component,
a large amount of the drug can be rapidly absorbed
percutaneously.
While the invention has been described in detail and with reference
to specific examples thereof, it will be apparent to one skilled in
the art that various changes and modifications can be made therein
without departing from the spirit and scope thereof.
* * * * *